11 research outputs found
Development of novel anilinoquinazoline-based carboxylic acids as non-classical carbonic anhydrase IX and XII inhibitors
As part of our ongoing endeavour to identify novel inhibitors of cancer-associated CA isoforms IX and XII as possible anticancer candidates, here we describe the design and synthesis of small library of 2-aryl-quinazolin-4-yl aminobenzoic acid derivatives (6a–c, 7a–c, and 8a–c) as new non-classical CA inhibitors. On account of its significance in the anticancer drug discovery and in the development of effective CAIs, the 4-anilinoquinazoline privileged scaffold was exploited in this study. Thereafter, the free carboxylic acid functionality was appended in the ortho (6a–c), meta (7a–c), or para-positon (8a–c) of the anilino motif to furnish the target inhibitors. All compounds were assessed for their inhibitory activities against the hCA I, II (cytosolic), IX, and XII (trans-membrane, tumour-associated) isoforms. Moreover, six quinazolines (6a–c, 7b, and 8a–b) were chosen by the NCI-USA for in vitro anti-proliferative activity evaluation against 59 human cancer cell lines representing nine tumour subpanels.</p
Benzoxaboroles as Efficient Inhibitors of the β‑Carbonic Anhydrases from Pathogenic Fungi: Activity and Modeling Study
A series
of 6-substituted benzoxaboroles were investigated as inhibitors
of the β-class carbonic anhydrase from three pathogenic fungi
(<i>Cryptococcus neoformans</i>, <i>Candida glabrata</i>, and <i>Malassezia globosa</i>). Independently from the
nature of the substituents on the phenyl of the urea/thiourea group,
all reported derivatives showed nanomolar inhibitory activities against
Can2 and CgNce103 vs micromolar inhibition against MgCA. Selectivity
over human CA I and CA II was noticed. The observed structure–activity
relationship trends have been rationalized by modeling study of selected
compounds into the active site of Can2 and MgCA. The present letter
demonstrates that benzoxaborole chemotype may offer interesting opportunities
for the inhibition of β-CA from pathogenic fungi and for the
development of antifungal agents with a new mechanism of action
Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase‑B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction
We report here the first dual inhibitors of brain carbonic
anhydrases
(CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer’s
disease. Classical CA inhibitors (CAIs) such as methazolamide prevent
amyloid-β-peptide (Aβ)-induced overproduction of reactive
oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also
implicated in ROS production, cholinergic system disruption, and amyloid
plaque formation. In this work, we combined a reversible MAO-B inhibitor
of the coumarin and chromone type with benzenesulfonamide fragments
as highly effective CAIs. A hit-to-lead optimization led to a significant
set of derivatives showing potent low nanomolar inhibition of the
target brain CAs (KIs in the range of
0.1–90.0 nM) and MAO-B (IC50 in the range of 6.7–32.6
nM). Computational studies were conducted to elucidate the structure–activity
relationship and predict ADMET properties. The most effective multitarget
compounds totally prevented Aβ-related toxicity, reverted ROS
formation, and restored the mitochondrial functionality in an SH-SY5Y
cell model surpassing the efficacy of single-target drugs
Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase‑B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction
We report here the first dual inhibitors of brain carbonic
anhydrases
(CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer’s
disease. Classical CA inhibitors (CAIs) such as methazolamide prevent
amyloid-β-peptide (Aβ)-induced overproduction of reactive
oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also
implicated in ROS production, cholinergic system disruption, and amyloid
plaque formation. In this work, we combined a reversible MAO-B inhibitor
of the coumarin and chromone type with benzenesulfonamide fragments
as highly effective CAIs. A hit-to-lead optimization led to a significant
set of derivatives showing potent low nanomolar inhibition of the
target brain CAs (KIs in the range of
0.1–90.0 nM) and MAO-B (IC50 in the range of 6.7–32.6
nM). Computational studies were conducted to elucidate the structure–activity
relationship and predict ADMET properties. The most effective multitarget
compounds totally prevented Aβ-related toxicity, reverted ROS
formation, and restored the mitochondrial functionality in an SH-SY5Y
cell model surpassing the efficacy of single-target drugs
Structural Characterization of Thiadiazolesulfonamide Inhibitors Bound to <i>Neisseria gonorrhoeae</i> α‑Carbonic Anhydrase
Drug-resistant Neisseria gonorrhoeae is a critical
threat to public health, and bacterial carbonic anhydrases expressed
by N. gonorrhoeae are potential new therapeutic targets
to combat this pathogen. To further expand upon our recent reports
of bacterial carbonic anhydrase inhibitors for the treatment of N. gonorrhoeae, our team has solved ligand-bound crystal
structures of the FDA-approved carbonic anhydrase inhibitor acetazolamide,
along with three analogs, in complex with the essential α-carbonic
anhydrase isoform from N. gonorrhoeae. The structural
data for the analogs presented bound to N. gonorrhoeae α-carbonic anhydrase supports the observed structure–activity
relationship for in vitro inhibition with this scaffold
against the enzyme. Moreover, the ligand-bound structures indicate
differences in binding poses compared to those traditionally observed
with the close human ortholog carbonic anhydrase II. These results
present key differences in inhibitor binding between N. gonorrhoeae α-carbonic anhydrase and the human carbonic anhydrase II isoform
Structural Characterization of Thiadiazolesulfonamide Inhibitors Bound to <i>Neisseria gonorrhoeae</i> α‑Carbonic Anhydrase
Drug-resistant Neisseria gonorrhoeae is a critical
threat to public health, and bacterial carbonic anhydrases expressed
by N. gonorrhoeae are potential new therapeutic targets
to combat this pathogen. To further expand upon our recent reports
of bacterial carbonic anhydrase inhibitors for the treatment of N. gonorrhoeae, our team has solved ligand-bound crystal
structures of the FDA-approved carbonic anhydrase inhibitor acetazolamide,
along with three analogs, in complex with the essential α-carbonic
anhydrase isoform from N. gonorrhoeae. The structural
data for the analogs presented bound to N. gonorrhoeae α-carbonic anhydrase supports the observed structure–activity
relationship for in vitro inhibition with this scaffold
against the enzyme. Moreover, the ligand-bound structures indicate
differences in binding poses compared to those traditionally observed
with the close human ortholog carbonic anhydrase II. These results
present key differences in inhibitor binding between N. gonorrhoeae α-carbonic anhydrase and the human carbonic anhydrase II isoform
Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase‑B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction
We report here the first dual inhibitors of brain carbonic
anhydrases
(CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer’s
disease. Classical CA inhibitors (CAIs) such as methazolamide prevent
amyloid-β-peptide (Aβ)-induced overproduction of reactive
oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also
implicated in ROS production, cholinergic system disruption, and amyloid
plaque formation. In this work, we combined a reversible MAO-B inhibitor
of the coumarin and chromone type with benzenesulfonamide fragments
as highly effective CAIs. A hit-to-lead optimization led to a significant
set of derivatives showing potent low nanomolar inhibition of the
target brain CAs (KIs in the range of
0.1–90.0 nM) and MAO-B (IC50 in the range of 6.7–32.6
nM). Computational studies were conducted to elucidate the structure–activity
relationship and predict ADMET properties. The most effective multitarget
compounds totally prevented Aβ-related toxicity, reverted ROS
formation, and restored the mitochondrial functionality in an SH-SY5Y
cell model surpassing the efficacy of single-target drugs
Design and synthesis of benzothiazole-based SLC-0111 analogues as new inhibitors for the cancer-associated carbonic anhydrase isoforms IX and XII
In this work, different series of benzothiazole-based sulphonamides 8a-c, 10, 12, 16a-b and carboxylic acids 14a-c were developed as novel SLC-0111 analogues with the goal of generating potent carbonic anhydrase (CA) inhibitors. The adopted strategy involved replacing the 4-fluorophenyl tail in SLC-0111 with a benzothiazole motif that attached to the ureido linker to produce compounds 8c and its regioisomers 8a-b. In addition, the ureido spacer was elongated by methylene or ethylene groups to afford the counterparts 10 and 12. In turn, the primary sulfamoyl zinc binding group (ZBG) was either substituted or replaced by carboxylic acid functionality in order to provide the secondary sulphonamide-based SLC-0111 analogues 16a-b, and the carboxylic acid derivatives 14a-c, respectively. All compounds (8a-c, 10, 12, 14a-c and 16a-b) were tested for their ability to inhibit CA isoforms CA I, II, IX and XII. Additionally, the in vitro anticancer properties of the developed CAIs were evaluated.</p
Identification of new 4-(6-oxopyridazin-1-yl)benzenesulfonamides as multi-target anti-inflammatory agents targeting carbonic anhydrase, COX-2 and 5-LOX enzymes: synthesis, biological evaluations and modelling insights
Multiple inhibitions of CA, COX-2 and 5-LOX enzymes has been recognised as a useful strategy for the development of anti-inflammatory drugs that can avoid the disadvantages of using NSAIDs alone. Here, we report new pyridazine-based sulphonamides (5a-c and 7a-f) as potential multi-target anti-inflammatory candidates. First, the furanone heterocycle in the dual CA/COX-2 inhibitor Polmacoxib was replaced with the pyridazinone one. Then, a hydrophobic tail was appended through benzylation of the 3-hydroxyl group of the pyridazinone scaffold to afford benzyloxy pyridazines 5a-c. Furthermore, the structures were adorned with the polar sulphonate functionality, in pyridazine sulphonates 7a-f, that are expected to be engaged in interactions with the hydrophilic half of the CA binding sites. All of the disclosed pyridazinones were tested for inhibitory activities against 4 hCA isoforms (I, II, IX, and XII), as well as against COX-1/2, and 5-LOX. Furthermore, in vivo anti-inflammatory and analgesic effects of pyridazinones 7a and 7b were examined.</p
Lipoyl-Homotaurine Derivative (ADM_12) Reverts Oxaliplatin-Induced Neuropathy and Reduces Cancer Cells Malignancy by Inhibiting Carbonic Anhydrase IX (CAIX)
Oxaliplatin (OXA) is a valuable and
largely used cancer drug which
induces a serious and intractable neuropathy. The lipoyl-homotaurine
derivative (<b>ADM_12</b>) reverts in vivo OXA-induced neuropathy,
and it is an effective antagonist of the nociceptive sensor channel
TRPA1. Unprecedentedly, this safe analgesic showed a synergy with
OXA in vitro and proved to inhibit CA IX, a relevant therapeutic target,
clearly interfering with pancreatic cancer cells’ aggressiveness